Percorrer por autor "Santos, Rita F."
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- Antibody blockade of the PSGL-1 immune checkpoint enhances T-cell responses to B-cell lymphomaPublication . Pereira, João L.; Arede, Liliana; Ferreira, Francisca; Matos, Andreia; Pereira, Dulcineia; Santos, Rita F.; Carmo, Alexandre M.; Oliveira, Maria J.; Machado, José C.; Duarte, Delfim; Santos, Nuno R. dos; Santos, Ana RitaDespite advancements in cancer immunotherapy, most lymphomas remain unresponsive to checkpoint inhibitors. P-selectin glycoprotein ligand-1 (PSGL-1), recently identified as a promoter of T-cell exhaustion in murine melanoma models, has emerged as a novel immune checkpoint protein and promising immunotherapeutic target. In this study, we investigated the potential of PSGL1 antibody targeting in B-cell lymphoma. Using allogeneic co-culture systems, we demonstrated that targeted antibody interventions against human PSGL-1 enhanced T-cell activation and effector cytokine production in response to lymphoma cells. Moreover, in vitro treatment of primary lymphoma cell suspensions with PSGL-1 antibody resulted in increased activation of autologous lymphoma-infiltrating T cells. Using the A20 syngeneic B-cell lymphoma mouse model, we found that PSGL-1 antibody treatment significantly slowed tumor development and reduced the endpoint tumor burden. This antitumoral effect was accompanied by augmented tumor infiltration of CD4+ and CD8+ T cells and reduced infiltration of regulatory T cells. Finally, antiPSGL-1 administration enhanced the expansion of CAR T cells previously transferred to mice bearing the aggressive Eμ-Myc lymphoma cells and improved disease control. These results demonstrate that PSGL-1 antibody blockade bolsters T-cell activity against B-cell lymphoma, suggesting a potential novel immunotherapeutic approach for treating these malignancies.
- Comprehensive assessment of environmental fungus-reactive T cells response in hypersensitivity pneumonitis patientsPublication . Santos, Rita F.; Coelho, Andreia L.; Rufo, João C.; Coelho, David; Gonçalves, Melany; Gonçalves, Samuel L.; Cunha, Cristina; Carvalho, Agostinho; Delgado, Luís; Morais, António; Saraiva, Margarida; Novais-Bastos, HélderHypersensitivity pneumonitis (HP) is an interstitial lung disease that results in parenchymal and small airways inflammation and culminates in breathlessness, negatively impacting patient’s quality of life and survival. HP is initiated by an exaggerated immune response triggered by the inhalation of a variety of environmental antigens. The identification of the triggering antigen is a cornerstone of the diagnostic algorithm, and importantly, exposure avoidance ameliorates the clinical outcomes. However, the inciting antigen is not identified in a large proportion of patients. A difficult to identify, but common inciting antigen, is exposure to household fungi.
- Decoding host-environment interactions in progressive pulmonary fibrosis: insights from hypersensitivity pneumonitisPublication . Meneses, Alexandra; Cardoso, Catarina G.; Coelho, David B.; Melo, Natália; Mota, Patrícia C.; Guimarães, Susana; Moura, Conceição S.; Carvalho, André; Sokhatska, Oksana; Beltrão, Marília; Delgado, Luís; Morais, António; Saraiva, Margarida; Bastos, Hélder N.; Santos, Rita F.Interstitial lung diseases (ILDs) comprise a heterogeneous group of parenchymal lung disorders characterized by diffuse infiltration of immune effector cells, fibroblasts, myofibroblasts, and extracellular matrix deposition at various pulmonary compartments. These conditions can progress to end-stage fibrosis, respiratory failure, and eventually, death. In 2020, we initiated the first national ILD registry and biobank under the FIBRALUNG project, which has enrolled over 950 cases to date, with over 40% of the cases being fibrotic ILDs. The most represented fibrotic ILD groups are Hypersensitivity Pneumonitis (HP) (46%), Idiopathic Pulmonary Fibrosis (IPF) (20%), and unclassifiable ILD (8%). HP is the leading cause of pulmonary fibrosis, nearly doubling the number of IPF cases, which contrasts with numbers from other countries. This underscores the importance of investigating non-IPF progressive pulmonary fibrosis within our setting. Longitudinal patient follow-up and biological sample collection were performed allowing patient stratification according to progression criteria. Our work so far has highlighted a potential role of CCL2-CCR2 axis in fibrotic HP disease progression. Elevated serum CCL2 strongly associated with disease progression and acute exacerbations, with baseline levels above 1080 pg/mL predicting oneyear progression/mortality. To complement these findings, we are conducting blood transcriptome analyses across different HP patient groups to identify progression-specific signatures. Simultaneously, lung microbiome profiling is underway to explore its role in fibrotic progression. These integrative approaches aim to uncover novel biomarkers and mechanistic pathways, paving the way for tailored therapeutic interventions.
- Signature cytokine-associated transcriptome analysis of effector γδ T cells identifies subset-specific regulators of peripheral activationPublication . Inácio, Daniel; Amado, Tiago; Pamplona, Ana; Sobral, Daniel; Cunha, Carolina; Santos, Rita F.; Oliveira, Liliana; Rouquié, Nelly; Carmo, Alexandre M.; Lesourne, Renaud; Gomes, Anita Q.; Santos, Bruno Silva; Santos, Ana Ritaγδ T cells producing either interleukin-17A (γδ17 cells) or interferon-γ (γδIFN cells) are generated in the mouse thymus, but the molecular regulators of their peripheral functions are not fully characterized. Here we established an Il17a-GFP:Ifng-YFP double-reporter mouse strain to analyze at unprecedented depth the transcriptomes of pure γδ17 cell versus γδIFN cell populations from peripheral lymph nodes. Within a very high fraction of differentially expressed genes, we identify a panel of 20 new signature genes in steady-state γδ17 cells versus γδIFN cells, which we further validate in models of experimental autoimmune encephalomyelitis and cerebral malaria, respectively. Among the signature genes, we show that the co-receptor CD6 and the signaling protein Themis promote the activation and proliferation of peripheral γδIFN cells in response to T cell antigen receptor stimulation in vitro and to Plasmodium infection in vivo. This resource can help to understand the distinct activities of effector γδ T cell subsets in pathophysiology.
- Unveiling common molecular pathways linked to ILDs with progressive fibrosing phenotype: the role of MUC5BPublication . Santos, Rita F.; Gonçalves, Melany; Mota, Patrícia Caetano; Cardoso, Catarina Gouveia; Coelho, Andreia L.; Sokhatska, Oksana; Beltrão, Marília; Guimarães, Susana; Delgado, Luís; Soares, Miguel; Morais, António; Saraiva, Margarida; Bastos, Hélder NovaisProgressive fibrosing ILDs (PF-ILDs) comprise a heterogeneous group of lung disorders associated with high morbidity and mortality, that exhibit a continuous worsening phenotype despite standard treatment. Among PF-ILDs are pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (HP), involving complex interactions between host genetics and different environmental triggers, shaping the immune milieu that ultimately drives the fibrotic cascade in a susceptible patient. The MUC5B promoter variant rs35705950 is the common genetic variant associated with the greatest risk of developing IPF. As IPF and fibrotic HP present phenotypic resemblances, we aim to analyze the role of rs35705950 MUC5B single nucleotide polymorphism (SNP) in common molecular pathways linked to PF-ILDs. Herein, taking advantage of our extensive ILD patients’ cohort, we found that MUC5B rs35705950 GT and TT genotypes frequency was dramatically increased in IPF and fibrotic HP compared to healthy controls.